Abstract

To explore the role of adult hippocampal neurogenesis in novelty processing, we assessed novel object recognition (NOR) in mice after neurogenesis was arrested using focal x-irradiation of the hippocampus, or a reversible, genetic method in which glial fibrillary acidic protein-positive neural progenitor cells are ablated with ganciclovir. Arresting neurogenesis did not alter general activity or object investigation during four exposures with two constant objects. However, when a novel object replaced a constant object, mice with neurogenesis arrested by either ablation method showed increased exploration of the novel object when compared with control mice. The increased novel object exploration did not manifest until 4-6 weeks after x-irradiation or 6 weeks following a genetic ablation, indicating that exploration of the novel object is increased specifically by the elimination of 4- to 6-week-old adult born neurons. The increased novel object exploration was also observed in older mice, which exhibited a marked reduction in neurogenesis relative to young mice. Mice with neurogenesis arrested by either ablation method were also impaired in one-trial contextual fear conditioning (CFC) at 6 weeks but not at 4 weeks following ablation, further supporting the idea that 4- to 6-week-old adult born neurons are necessary for specific forms of hippocampal-dependent learning, and suggesting that the NOR and CFC effects have a common underlying mechanism. These data suggest that the transient enhancement of plasticity observed in young adult-born neurons contributes to cognitive functions.

(A) Schematic diagram of the NOR paradigm. Mice received 4 exposures to two objects. For exposure 5, one of the objects was replaced with a novel object. (B) Mice were x-irradiated or sham-irradiated at 9 weeks of age and the NOR paradigm was administered 8 weeks later at 17 weeks of age. (C–D) General activity and investigation (habituation; averaged across both objects) declined across exposures 1–4 for both x-irradiated and sham mice. There was no effect of x-irradiation on either variable [F’s(1,19) < 1]. In exposure 5 (replacement), x-irradiated mice investigated the novel object more than sham mice (p = 0.02), but the groups did not differ in exploration of the constant object (p = 0.42). General activity during exposure 5 was not affected by x-irradiation (p = 0.11). (F) The latency to investigate the novel object was shorter than the latency to investigate the constant object for both groups of mice (p < 0.01), and the latencies did not differ between groups (p = 0.36). * p < 0.05. ** p < 0.01. Error bars represent ± SEM.

NOR performance is related to the length of time after x-irradiation rather than the absolute age of the mouse

(A) Schematic diagram of the experimental time-course. (B–C) X-irradiated and sham mice did not differ in general activity or investigation (habituation) during exposures 1 through 4 [F’s(1,18) < 2.4, p’s > 0.14]. Both groups of mice investigated the novel object more than the constant object [F(1,22) = 24.3, p < 0.001], and there was no effect of the x-irradiation treatment [F’s(1,22) < 1]. Error bars represent ± SEM.

(A) Schematic diagram of the experimental time-course. Mice were pre-exposed to the arena before introduction of the objects. (B–C) Pre-exposure to the arena increased overall levels of object investigation in both groups of mice when a novel object was introduced; however, both groups explored the constant and novel object similarly (n = 6–8 mice/group). Error bars represent ± SEM.

(A) Schematic diagram of the experimental time-course. Mice were treated with GCV for 28 days and then were tested in the NOR paradigm 2 weeks later. (B) GCV treatment did not induce body weight loss as indicated by comparable body weights between GFAP-TK TG and WT mice before and after GCV treatment. (C) DCX+ young neurons were significantly reduced in GFAP-TK TG mice treated with GCV when compared with WT mice, indicating that GCV had significantly reduced neurogenesis. (D) Representative images of the DG processed for DCX immunoreactivity. (E–F) During exposures 1 through 4, WT and GFAP-TK TG mice exhibited similar levels of general activity [F(1,44) = 1.4, p = 0.25] and investigation [F(1,44) = 1.3, p = 0.255]. In exposure 5, GFAP-TK TG mice explored the novel object more than WT mice [t(44) = 2.1, p = 0.041], but the groups did not differ in investigation of the constant object (p = 0.453). (G) The latency to the novel object was shorter than that to the constant object for both groups of mice (p < 0.01). There was no effect of genotype on the latency to either object (p = 0.87). * p < 0.05. ** p < 0.01. Error bars represent ± SEM.

Cells aged 4–6 weeks old modulate NOR and CFC performance. At this time point, adult-born neurons have unique features that enhance plasticity, such as elevated expression of NR2B-containing NMDA receptors (). NR2B-containing NMDA receptors are denoted as red and black subunits.